Long-term sustained-release preparation

ABSTRACT

A solid sustained-release preparation in the form of a needle-like or bar-like shape, which consists essentially of an active ingredient and a pharmaceutically acceptable biodegradable carrier (e.g. proteins, preferably collagen, gelatin, and a mixture thereof). The sustained-release preparation can be administered to the body or implanted into the body by injection or an injection-like method and can release the active ingredient at an effective level for a long period of time when administered.

This is a continuation-in-part application of Ser. No. 660,052 filed onOct. 12, 1984, now abandoned.

The present invention relates to a long-term sustained-releasepreparation. More particularly, it relates to a long sustained-releasepreparation in the form of a bar-like or needle-like shaped preparationsuitable for injection or injection-like administration, which comprisesan active ingredient in admixture with one or more of pharmaceuticallyacceptable biodegradable carriers which can be implanted into the body.The preparation of the invention is particularly suitable formedicaments which are unstable to heat.

It is known to prepare a medicament embraced within a polymer, forexample polyethylene glycol diacrylate polymer, and to implant theproduct into the body in order to sustain the release of the medicament.However, such a technique has various problems in that the polymer isnot biodegradable and hence it must be removed by suitable means afteradministration and the implanting must be done by an operation withtroublesome treatment. Nevertheless, it has been desired to make asustained-release preparation of many medicaments.

The present inventors have intensively studied on an improvedsustained-release preparation or medicaments, and have found that thedesired sustained-release preparation can be obtained by admixing anactive ingredient with a specific biodegradable carrier and that theformed product of the preparation in the form of a bar-like orneedle-like shape is very useful for injection or implanting into thebody and can show excellent effect for release-sustaining of the activeingredient.

An object of the present invention is to provide an improvedsustained-release preparation. Another object of the invention is toprovide a long-term sustained-release preparation in the form of abar-like or needle-like shaped preparation which can injected orimplanted into the body and can release the active ingredient and canmaintain the desired level of the active ingredient in blood or inlesional region for a long period of time. A further object of theinvention is to provide a method for preparing the sustained-releasepreparation as set forth above without using any specific binding agentand without heating. A still further object of the invention is toprovide a device for administering a sustained-release preparation inthe form of a needle-like or bar-like shape. These and other objects andadvantages of the present invention will be apparent to persons skilledin the art from the following description.

The sustained-release preparation of the present invention in the formof a bar-like or needle-like shaped preparation consists essentially of(i) an active ingredient in admixture with (ii) one or more ofpharmaceutically acceptable biodegradable carriers which can be absorbedor be subject to enzymolysis in body and can be implanted within thebody. The sustained-release preparation is formed in a bar-like orneedle-like shape and can be injected or implanted into the body.

The active ingredient used in the present invention is not specified,but includes particularly medicaments which are effective in a verysmall amount and in which their activity is promoted by sustainedrelease, and more particularly medicaments which are unstable to heat.Suitable examples of the active ingredient are tissue plasminogenactivator, prostaglandins, prostacyclines, various bio-hormones,interferons, interleukins, tumor necrosis factor, and some othercytokines (e.g. macrophage activating factor, migration inhibitoryfactor and colony stimulating factor). The term bio-hormones meanssubstances which are produced within the living body and regulate thebio-functions, including growth hormone (GH) such as human growthhormone (HGH), bovine growth hormone (bGH) including biosyntheticproduct (B-HGH, etc.); growth hormone releasing factors (GRF) which areknown as peptides consisting of a number of amino acids of 44, 40, 37 or29 (e.g. hGRF(1-44)NH₂, hGRF(1-29)NH₂); somatomedines (SM) such as SM-A,SM-B, SM-C, insulin-like growth factor (IGF)-I, IGF-II, andmultiplication stimulating activity (MSA); and calcitonin (i.e. calciumregulating hormone secreted from the mammalian thyroid gland and innon-mammalian species from the ultimobranchial gland).

Interferon, interleukin, tumor necrosis factor, and some other cytokinesare somewhat different each other, but are common in that they have verysimilar molecular weight, are glycoproteins or proteins and have similarpharmacological and physicochemical properties as those of α-interferonas shown in experiments as disclosed hereinafter. All of these compoundsare prepared in the desired excellent sustained-release preparation ofthe present invention.

The above active ingredients may be used alone or in combination of twoor more thereof.

The biodegradable carrier used in the present invention means a carrierwhich can easily be absorbed or be subject to enzymolysis in body andcan be implanted into the body. Suitable examples of the biodegradablecarrier are proteins such as collagen, gelatin, albumin, or the like.These substances can be used alone or in any combination of two or morethereof, but in view of moldability, collagen or gelatin or a mixturethereof are preferable. Collagen is a protein which is a main protein ofconnective tissue of animals, has less antigenicity, and hence, haswidely been used as a safe operation yarn in various medical operations.The collagen may be an atelocollagen having far less antigenicity whichis obtained by removing the telopeptide region by treating collagen withan enzyme (e.g. pepsin) in order to make it safer. Gelatin is a proteinderived from collagen. Gelatin is a high molecular weight amphotericelectrolyte which has less antigenicity and the properties of beingconvertible between sol and gel forms, is inexpensive, and hence it hasalready been confirmed as a safe substance for medical use.

The medicaments and carriers used in the present invention arepreferably purified products, but commercially available products may beused as purchased. The commercially available medicaments and carrierscontain usually some appropriate additives such as stabilizers andbuffering agents to some extent. For instance, an aqueous collagensolution contains usually a buffer of inorganic or organic salts, suchas a phosphate buffer, citrate buffer or acetate buffer. Commerciallyavailable interferons contain usually sodium chloride and further humanserum albumin, amino acids (e.g. glycine, alanine, etc.), succharides(e.g. glucose, etc.), sugar-alcohols (e.g. mannitol, xylitol, etc.).Other medicaments occasionally contain fetal cow serum, bovine serumalbumin, phosphate buffered saline, Tris, etc. These products may beused as obtained, but in view of release-sustaining properties, it ispreferable to remove such additives or other components.

The preparation of the present invention contains the active ingredientin an amount in which the active ingredient is usually used. Forexample, interferon is usually contained in an amount of 10⁴ to 10⁹ IU,preferably 10⁵ to 5×10⁸ IU per dosage unit.

The ratio of the medicament and the carrier is not specified, but forexample, interferon is preferably incorporated in an amount of 10³ to10⁸ IU per 1 mg of the carrier.

One of the characteristics of the present invention is in that thepreparation can be prepared without using any specific binding agent andfurther without heat treatment through the steps. The preparation is,therefore, particularly suitable for medicaments which are unstable toheat.

The sustained-release preparation of the present invention can beprepared by the following method.

An active ingredient or an aqueous solution thereof is mixed with abiodegradable carrier or an aqueous solution thereof, and the mixture ishomogeneously mixed by stirring while preventing the occurrence of foamas much as possible. By the mixing of the active ingredient and thecarrier in the state of a liquid, the active ingredient is incorporatedinto the carrier matrix. Thereafter, the mixture is dried in order toproduce a shaped product having an enough strength for administering toa living body. The drying method is not specified, but it may be dried,for example, by allowing to stand, or by spray-drying or lyophilization.In addition, the mixture may optionally be concentrated at a lowtemperature before drying, for example, by allowing the solution tostand at room temperature. In the above steps, the mixing step anddrying step are usually carried out at room temperature or lower andoptionaly under cooling. For instance, the mixing step is usuallycarried out at about 5° C. to 30° C.; the drying by lyophilization isusually carried out at -50° C. to 0° C.; and the drying by allowing tostand or by spray-drying is usually carried out at room temperature orlower (i.e. about 15° C. to 30° C.). The spray-dry is usually carriedout by controlling the temperature of the solution and vessel at roomtemperature or lower, by which the temperature of the active ingredientcan be kept at room temperature or lower and hence no damage is causedto the active ingredient even though it is unstable to heat.

The preparation of the present invention preferably consistssubstantially of an active ingredient and a biodegradable carrier. Thatis, when components other than the active ingredient and carrier arepresent in the preparation of the invention, they occasionally promotethe release of active ingredient, and hence, it is preferable not toincorporate such other components as much as possible. However, from thepractical viewpoint, the preparation may contain other componentsoriginating from the commercially available medicaments and carriersunless they substantially affect the release-sustaining properties.Likewise, the preparation of the invention may pharmaceuticallyacceptable conventional stabilizers, preservatives, and local anestheticagents unless they substantially affect the release-sustainingproperties.

The preparation thus obtained is optionally pulverized into powdersunder cooling with dry ice or liquid nitrogen so that the preparation iskept at about -10° C. to about -100° C., or any other conventionalpulverization methods at room temperature or lower temperature. Thepowder is optionally compressed to form some specific shapes, such as aneedle-like or fine bar-like shaped preparation (in case of preparationfor human, diameter: about 0.5 mm-5 mm, preferably 0.5 mm-1.5 mm,length: about 5 mm-50 mm, preferably, 5 mm-15 mm; in case of preparationfor other animals, diameter: about 0.5 mm-10 mm, preferably 0.5 mm-5 mm,length: about 5 mm-100 mm, preferably 5 mm-50 mm), which can be insertedinto a body by operation or with a forceps needle for fiberscope, anindwelling needle, or other appropriate administration device asmentioned hereinafter. Alternatively, the powdery preparation is placedinto a mold, followed by concentrating at a low temperature, asmentioned hereinbefore, or by lyophilizing to compress and form it intoa needle-like or a fine bar-like shaped preparation.

Through all the steps for preparing the desired sustained-releasepreparations, the procedure is carried out under sterilized conditionsbecause the preparations are to be used as an injection or forimplanting into a body.

The long sustained-release preparation of the present invention can beadministered to human patients or other animals such as cattle, sheep,pig, rabbit, hen and cock, and the like by operation or by other variousmethods, for example, by inserting a fine tube into the body at thedesired region with an appropriate means, such as catheter, and theninserting the needle-like shaped preparation of the present invention bypassing through the inside of the fine tube, or by inserting thepreparation of the present invention directly into the body at thelesional region by means of forceps needle of fiberscope.

The present invention provides also an improved device for administeringthe needle-like or bar-like shaped preparation of the present invention.

The device for administration of the sustained-release preparation andadministration manner are explained referring to the accompanyingdrawings.

FIG. 1 shows an embodiment of a device for administering the preparationof the present invention which comprises a fine tube and an innerneedle.

FIG. 2 is an embodiment showing the state that the device as shown inFIG. 1 is stabbed into the body.

FIG. 3 is an embodiment showing the state that a needle-like shapedsolid preparation is administered into the body by the device as shownin FIG. 1.

FIG. 4 shows an embodiment of a needle for administering a needle-likeshaped solid preparation of the present invention wherein the solidpreparation is held.

FIG. 5 is an embodiment showing the state that the needle-like shapedsolid preparation is administered into the body with the administrationneedle as shown in FIG. 4.

FIG. 6 is an embodiment of a needle for administering a needle-likeshaped solid preparation of the present invention which is provided witha removable cover for preventing the held solid preparation from fallingdown.

FIG. 7 is a graph showing the relation of the blood level of an activeingredient and time elapsed after intramuscular administration of thepreparation in rabbits.

The device for administering a needle-like shaped preparation comprises(i) a fine tube and (ii) an inner needle which can freely slide withinthe fine tube.

The fine tube in the above device is a tube having an inner diameter of0.5 to 10 mm which can be inserted partly into a body. The length of thetube is not specified but may be any size convenient for injection, andis usually in the range of 2 cm to 10 cm. The material for preparing thetube may be any kind of material compatible with the body. The innerneedle has a sharp tip as shown in the accompanying FIG. 1 and has anouter diameter as the same as or smaller than the inner diameter of thefine tube.

The device for administering a needle-like shaped preparation is usuallyheld in a holding device (6) in use, but may be used by being held atthe tip of forceps needle of fiberscope.

The administration manner of the needle-like shaped preparation with theabove device is explained in more detail below. Firstly, the innerneedle (1) is stabbed into a portion of the body (2) and simultaneouslythe fine tube (3) is inserted into the body by sliding its inner wallalong the outer wall of the inner needle (1) (cf. the accompanying FIG.2). Thereafter, the inner needle (1) is pulled off, and then theneedle-like shaped preparation (4) is inserted into the body by passingit through the inner slit of the fine tube (3), and finally the finetube is removed. The insertion of the needle-like shaped preparationinto the body is usually carried out by inserting the preparation intothe fine tube after pulling off of the inner needle (1), pushing thepreparation with a pushing pole (5) into the inside of the body (2) (cf.the accompanying FIG. 3). The pushing pole (5) may be any pole which canbe inserted into and can freely slide inside the fine tube (3), and theabove inner needle (1) may also be used as the pushing pole.

In order to insert the preparation of the present invention into a deepregion of the body, i.e. internal organs such as the stomach wall, thedevice for a fiberscope may be used. Easy handling for a fiberscope caneffect procedures such as stabbing of an inner needle, insertion of thefine tube, pulling off of the inner needle, administration of thepreparation and taking off of the fine tube.

The preparation which can be administered by the above device may be anyneedle-like or bar-like shaped preparation which can be inserted andheld within the fine tube (3).

An alternative device for insertion of a needle-like shaped solidpreparation is an injection needle provided with a inner pushing polewhich can smoothly slide within the slit of the needle. The injectionneedle includes the conventional injection needle, and the pushing polehas an outer diameter which is equal to or smaller than the innerdiameter of the injection needle and can push the needle-like shapedsolid preparation having a diameter of 0.5 to 10 mm.

The device for insertion of a needle-like shaped solid preparation maybe held with conventional holding device (7), but may be used by holdingit at the tip of a forceps needle for a fiberscope.

The administration of the needle-like shaped solid preparation of thepresent invention is explained in more detail below.

Initially, the needle-like shaped solid preparation (9) is held withinthe injection needle (8) (cf. the accompanying FIG. 4), the injectionneedle (8) is stabbed into the portion of the body (11) andsimultaneously the preparation is administered into the body (11) bypushing it with a pushing pole (10) (cf. the accompanying FIG. 5). Inorder to administer the preparation to a deep region of the body such asthe stomach wall, it may be administered with a fiberscope as mentionedabove. In such a case, to prevent the preparation from falling out ofthe needle, it is preferable to provide a removable cover (12) at thetip of the needle (cf. the accompanying FIG. 6). The solid preparationuseful for the above administration may be in any form such asneedle-like or bar-like shape which can be held in a conventionalinjection needle.

As explained above, according to the device for injection of the presentinvention, the preparation of the present invention can easily beadministered, for example, into internal organs with a fiberscope, andsystematically or topically at the body surface by operation or with adevice or needle as mentioned above. These methods are practically andclinically very useful, and it is a novel idea that a biodegradablesolid preparation is administered in the above-mentioned manner.

The present invention is illustrated by the following Experiments andExamples, but should not be construed to be limited thereto.

EXPERIMENT 1

There were used as the test samples a needle-shaped preparation ofα-interferon-collagen prepared in Example 1 disclosed hereinafter(Sample A) and a reference (an aqueous injection of α-interferonoriginated from Namalwa cells). The test samples were each administeredintramuscularly to rabbit, and the change of level in blood of theactive ingredient with lapse of time was measured by RIA(radioimmunoassay) method. Two rabbits were used for each sample, andthe test samples were each administered in a dose of 10⁶ U/kg. The bloodlevel is shown as an average in two rabbits.

The results are shown in the accompanying FIG. 7. In FIG. 7, is thegraph of Sample A, and is that of reference (α-interferon aqueousinjection). As is clear from the figure, the Sample A showedrelease-sustaining properties, and even after 48 hours, the blood levelof several tens unit/ml was maintained.

Thus, it is suggested by in vivo tests using rabbits that thepreparation of the present invention is useful clinically.

EXAMPLE 1

An aqueous solution of α-interferon (titer: 4.9 MU/ml) (100 ml) and 2 %atelocollagen (50 g) are homogeneously mixed with stirring whilepreventing occurrence of foam as much as possible. The mixture islyophilized and pulverized at a low temperature using liquid nitrogen.The pulverized product thus obtained is formed under compression to givea needle-shaped sustained-release preparation (A) wherein interferon iscontained in an amount of 10 MU per 1 needle.

EXAMPLE 2

A commercially available aqueous solution of α-interferon (α-interferontiter 4.9 MU/ml, human serum albumin 1.5 mg/ml) (100 ml) and 2 %atelocollagen (50 g) are homogeneously mixed while preventing occurrenceof foam as much as possible. The mixture is lyophilized and pulverizedat a low temperature using liquid nitrogen. The pulverized product thusobtained is subjected to compression molding to give a needle-likeshaped sustained-release preparation (Sample B) wherein interferon iscontained in an amount of 10 MU per 1 needle.

EXAMPLE 3

An aqueous solution of α-interferon (titer, 4.9 MU/ml) (100 ml) and 2 %collagen (50 g) are homogeneously mixed while preventing occurrence offoam as much as possible. The mixture is lyophilized and pulverized at alow temperature using liquid nitrogen. The pulverized product thusobtained is subjected to a compression molding to give a bar-like shapedsustained-release preparation (Sample C) wherein interferon is containedin an amount of 5 MU per 1 bar.

EXAMPLE 4

An aqueous solution of α-interferon (titer, 4.9 MU/ml) (100 ml) andatelocollagen powder (1 g) are mixed and the mixture is dissolved byadding thereto 0.1 N hydrochloric acid, and the resulting solution isentered into a mold and lyophilized. The lyophilized product is formedunder compression to give a needle-shaped sustained-release preparation(Sample D) wherein interferon is contained in an amount of 10 MU per 1needle.

EXAMPLE 5

B-HGH (biosynthetic human growth hormone containing glycine 800 mg) (100IU) is dissolved in 10 % aqueous gelatin solution (3 ml). The mixture islyophilized and pulverized at a low temperature using liquid nitrogen.The pulverized product is compressed in a mold to give a needle-likeshaped, sustained-release preparation.

EXAMPLE 6

hGRF(1-29)NH₂ (i.e. human growth hormone-releasing factor) (1 mg) isdissolved in 2 % aqueous atelocollagen solution (2 ml). The mixture islyophilized and pulverized at a low temperature using liquid nitrogen.The pulverized product is compressed in a mold to give a bar-likeshaped, sustained-release preparation.

EXAMPLE 7

Gelatin (10 g) is dissolved in distilled water (100 ml). To the solution(5 ml) is added IGF-1 (insulin-like growth factor-1) (20 mg), and themixture is lyophilized and pulverized at a low temperature using liquidnitrogen to obtain a powder. The powdery product is compressed in a moldto give a needle-like shaped, sustained-release preparation.

EXAMPLE 8

Collagen (10 g) is dissolved in an aqueous solution (100 ml) containing1×10⁵ U of human GM-CSF (granulocyte-macrophage-colony stimulatingfactor), and the solution is lyophilized and pulverized at a lowtemperature using liquid nitrogen. The pulverized product is compressedin a mold to give a bar-like shaped sustained-release preparation.

What is claimed is:
 1. A method for the preparation of a solidsustained-release preparation, which comprises mixing under aqueousconditions a physiologically active ingredient that is unstable to heatand a pharmaceutically acceptable biodegradable protein carrier toincorporate the active ingredient in a carrier matrix to a degreesufficient to provide sustained-release properties; drying the resultingmixture; and then forming the dried material into the form of aneedle-like or bar-like shape.
 2. The method according to claim 1,wherein said biodegradable carrier is collagen, atelocollagen orgelatin.
 3. The method according to claim 2, wherein said biodegradablecarrier is collagen.
 4. The method according to claim 1, wherein saidactive ingredient is a member selected from the group consisting oftissue plasminogen activator, prostaglandins, prostacyclines,bio-hormones, interferons, interleukins, tumor necrosis factor and othercytokines.
 5. The method according to claim 1, wherein said activeingredient is a member selected from the group consisting ofinterferons, interleukins, tumor necrosis factor, growth hormone, growthhormone releasing factor, somatomedines, calcitonin, macrophageactivating factor, migration inhibitory factor, and colony stimulatingfactor.
 6. The method according to claim 1, wherein said mixing isconducted at a temperature of from 5° to 30° C.
 7. The method accordingto claim 1, wherein said drying is conducted at a temperature of from15° to 30° C.
 8. The method according to claim 6, wherein said drying isconducted at a temperature of from 15° to 30° C.
 9. The method accordingto claim 1, wherein said drying is performed by lyophilization at atemperature of from -50° C. to 0° C.
 10. The method according to claim9, wherein the product obtained from said lyophilization is subjected topulverization at a temperature of from -100° C. to about roomtemperature.
 11. The method according to claim 4, wherein saidbiodegradable carrier is collagen.
 12. The method according to claim 5,wherein said biodegradable carrier is collagen.
 13. The method accordingto claim 6, wherein said biodegradable carrier is collagen.
 14. Themethod according to claim 7, wherein said biodegradable carrier iscollagen.
 15. The method according to claim 8, wherein saidbiodegradable carrier is collagen.
 16. The method according to claim 1,wherein said sustained-release preparation is prepared without the useof any binding agent.
 17. The method according to claim 3, wherein saidsustained-release preparation is prepared without the use of any bindingagent.
 18. The method according to claim 8, wherein saidsustained-release preparation is prepared without the use of any bindingagent.
 19. The method according to claim 10, wherein saidsustained-release preparation is prepared without the use of any bindingagent.
 20. The method according to claim 14, wherein saidsustained-release preparation is prepared without the use of any bindingagent.